Systemic lupus Erythematosus is a prototypic autoimmune disease affecting multiple systems. This disease causes significant morbidity and mortality. The University of Virginia Specialized Center of Research in Systemic Lupus Erythematosus (UVa SCOR in SLE) was established in July 1998 with funding from the NIAMS. The Center has successfully fostered a multi-discipline approach to study the pathogenesis of this disease. The consortiums between the University of Virginia and the Mayo Clinic and the Johns Hopkins Hospital have strengthened the SCOR. Studies on a new strain of lupus- prone mice NZM2328 have led to the identification of new SLE susceptibility loci, the distinction between acute and chronic glomerulonephritis, and most importantly the dissociation of ANA, anti-dsDNA and anti-nucleosome antibody production from chronic glomerulonephritis. Significant information has been obtained regarding the mechanism of epitope spreading in the autoantibody diversification to SLE-related autoantigens. The identification of crossreactive T cells is a major advance in the understanding of this process. Two 3-day thymectomy models to study the role of CD25+ regulatory T cells have been developed. Models for Sjogren's syndrome/autoimmune sialoadenitis have been created. Studies of the DR and DQ transgenic mice provide evidence for the importance of the DR antigens in determining the specificities of the autoantibodies produced. Studies involving serial patient samples provide evidence for fluctuation of autoantibody titers without clear correlation with patients' clinical courses. A collaboration between the University of Virginia and the National Institute of Immunology in India has established a program to study the role of DR in the generation of anti-Sm antibody responses by exploring the ethnic and environmental differences between the India and the U.S. populations. Studies on the role of estrogen receptors in the pathogenesis of SLE show interesting preliminary data. These advances form the basis for the competitive renewal. The competitive renewal application will continue to develop the interdisciplinary approach to study the immunological, genetic and environment factors important in the pathogenesis of SLE. The SCOR renewal application has four projects and three cores. The projects are 1) HLA-D Molecules, T Cell Epitopes and Autoantibody Specificities in SLE; 2) Regulatory and Effector T Cells in SLE; 3) Genetic Control in Lupus-prone NZM2328; and 4) Estrogen Receptors in SLE and the UVa Lupus Cohort. The proposed studies are to provide experimental evidence to support the stated hypothesis that molecular mimics (environmental factors) may initiate an autoimmune response, and the diversification of the autoimmune response with inflammation leads to end-organ damage in appropriate hosts. The three cores are 1) Administrative Core, 2) Cell Sciences and Immunochemistry Core, and 3) Mouse Genetics Core. These cores will serve all the projects and will continue to facilitate interaction among investigators within the UVa SCOR in SLE. The SCOR continues to represent both inter- and intra-institutional collaboration. It is expected that this interactive approach will continue to provide new insights into the immunological and genetic factors important in SLE.